贞芪扶正颗粒联合化疗治疗胃癌的临床研究

目的:观察贞芪扶正颗粒联合化疗治疗胃癌的的临床疗效.方法:80例胃癌术后的病人随机分为2组.贞芪扶正组(贞芪扶正颗粒加化疗)40例,对照组(单纯化疗)40例.观察治疗前后卡氏评分、外周血常规和血液流变学的变化,并观察自然杀伤(NK)细胞、T淋巴细胞亚群、可溶性白介素-2受体(SIL-2R)等指标的变化.结果:贞芪扶正组胃癌患者化疗后生存质量改善,外周WBC,RBC稳定,单纯化疗组外周WBC,RBC,Hb均较化疗前明显下降;贞芪扶正组化疗后患者NK细胞活性、CD3 ,CD4 T细胞数和CD4 /CD8 比值升高,血清SIL-2R的浓度明显下降;而单纯化疗组化疗后患者NK细胞活性、CD4 T细胞数和CD4 /CD8 比值下降,血清SIL-2R的浓度升高.结论:贞芪扶正颗粒联合化疗对胃癌术后的患者机体免疫功能有保护和促进作用,并能防治化疗引起的骨髓抑制.     

川芎嗪对顺铂肾损伤大鼠肾细胞凋亡及凋亡相关蛋白表达的影响

目的探讨川芎嗪(TMP)对顺铂(DDP)大鼠肾毒性有无保护作用。方法DDP8mg·kg-1ip诱导大鼠肾损伤,于给予DDP2d前大鼠分别ip50,100mg·kg-1·d-1TMP,连续5d,于给药d5收集各组大鼠尿液,测24h尿蛋白含量,并于末次给药后4h处死大鼠,测血清尿素氮(BUN)和肌酐(Cr)含量,采用原位缺口末端标记法检测肾脏细胞凋亡,免疫组化SP法检测肾脏Bax和Bcl2蛋白表达水平。结果50,100mg·kg-1TMP组可降低DDP所致大鼠24h尿蛋白及血清BUN和Cr含量的升高(P<0.01);TMP两剂量组也可明显减少肾脏细胞凋亡率(P<0.01),显著增强肾脏凋亡相关蛋白Bcl2的表达,减少Bax表达,并明显降低Bax/Bcl2比值(P<0.01)。结论TMP可能通过降低凋亡相关蛋白Bax和增强Bcl2的表达,并降低Bax/Bcl2比值而抑制DDP引起的肾细胞凋亡,使肾脏免受损伤的作用。     

The effect of divalent cations on neuronal nitric oxide synthase activity.

Neuronal nitric oxide synthase (NOS I) is a Ca(2+)/calmodulin-binding enzyme that generates nitric oxide (NO*) and L-citrulline from the oxidation of L-arginine, and superoxide (O(2)*(-)) from the one-electron reduction of oxygen (O(2)). Nitric oxide in particular has been implicated in many physiological processes, including vasodilator tone, hypertension, and the development and properties of neuronal function. Unlike Ca(2+), which is tightly regulated in the cell, many other divalent cations are unfettered and can compete for the four Ca(2+) binding sites on calmodulin. The results presented in this article survey the effects of various divalent metal ions on NOS I-mediated catalysis. As in the case of Ca(2+), we demonstrate that Ni(2+), Ba(2+), and Mn(2+) can activate NOS I to metabolize L-arginine to L-citrulline and NO*, and afford O(2)*(-) in the absence of L-arginine. In contrast, Cd(2+) did not activate NOS I to produce either NO* or O(2)*(-), and the combination of Ca(2+) and either Cd(2+), Ni(2+), or Mn(2+) inhibited enzyme activity. These interactions may initiate cellular toxicity by negatively affecting NOS I activity through production of NO*, O(2)*(-) and products derived from these free radicals.     

Glutathione depletion is a major determinant of inhaled naphthalene respiratory toxicity and naphthalene metabolism in mice.

Naphthalene (NA) is metabolized to highly reactive intermediates that are primarily detoxified by conjugation to glutathione (GSH). Intraperitoneal administration of naphthalene causes substantial loss of both hepatic and respiratory GSH, yet only respiratory tissues are injured in mice. The liver supplies GSH to other organs via the circulation, making it unclear whether respiratory GSH losses reflect in situ respiratory depletion or decreased hepatic supply. To address this concern, mice were exposed to naphthalene by inhalation (1.5-15 ppm; 2-4 h), thereby bypassing first-pass hepatic involvement. GSH levels and histopathology were monitored during the first 24 h after exposure. Half of the mice were given the GSH depletor diethylmaleate (DEM) 1 hour before naphthalene exposure. Lung and nasal GSH levels rapidly decreased (50-90%) in mice exposed to 15 ppm naphthalene, with cell necrosis throughout the respiratory tract becoming evident several hours later. Conversely, 1.5 ppm naphthalene caused moderate GSH loss and only injured the nasal olfactory epithelium. Neither naphthalene concentration depleted hepatic GSH. Animals pretreated with DEM showed significant GSH loss and injury in nasal and intrapulmonary airway epithelium at both naphthalene concentrations. DEM treatment, perhaps by causing significant GSH loss, decreased water-soluble naphthalene metabolite formation by 48% yet increased NA-protein adducts 193%. We conclude that (1) GSH depletion occurs in airways independent of hepatic function; (2) sufficient GSH is not supplied by the liver to maintain respiratory GSH pools, or to prevent injury from inhaled naphthalene; and (3) GSH loss precedes injury and increases protein adduct formation.     

竹叶抗氧化物急性和亚慢性毒性研究

目的进行竹叶抗氧化物的急性和亚慢性毒性试验,为其食用提供安全性毒理学评价依据.方法设1.00、2.15、4.64和10.0g/kg体重三剂量组,进行急性毒性研究:设1.43、2.87和4.30g/kg体重三个剂量组,进行亚慢性毒性研究.结果竹叶抗氧化物雌、雄性大鼠经口LD50均大于10.0g/kg体重;大鼠90天喂养试验各剂量组各项指标均未见明显毒性反应.结论在本实验条件下,竹叶抗氧化物按急性毒性分类属实际无毒类;按大鼠90天喂养试验结果,其最大无作用剂量为4.30g/kg体重.     

电磁辐射对生物体的生物学效应

近年来,在职业场所或在家中,电磁辐射的存在越来越广泛.电磁辐射可对生物体具有致伤效应,目前已成为医学领域的重大研究课题.该文就细胞毒性、基因毒性、外遗传毒性这三条基本途径,对电磁辐射引起生物学效应的可能机制作一概要综述.     

国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期临床观察

目的 甲磺酸伊马替尼作为治疗慢性粒细胞白血病(chronic myelogenous leukemia,CML)-慢性期(chronic phase,CP)患者的一线治疗药物,国产药物应用的安全性和有效性尚缺乏系统评价参考.本研究探讨国产甲磺酸伊马替尼治疗初诊CML-CP患者的早期血液学、细胞遗传学、分子学反应与安全性.方法 收集2014-03-01-2015-10-31就诊于新疆自治区人民医院血液科的43例初诊CML-CP患者,给予国产甲磺酸伊马替尼(昕维?R)400 mg/d口服,治疗3、6、12个月时进行骨髓细胞学、染色体、FISH与骨髓BCR-ABL融合基因转录本水平评估,观察评估患者血液学反应、细胞遗传学反应和分子学反应及安全性.结果 43例患者治疗满3个月时,42例(97.7%)达完全血液学反应(complete hematologic response,CHR);35例(81.4%)达主要细胞遗传学反应(major cytogenetic response,MCyR),其中11例(25.6%)达完全细胞遗传学反应(complete cytogenetic response,CCyR);30例(69.8%)达国际标准化BCR-ABL转录本水平(BCR-ABLIS)≤10%,4例(9.3%)达BCR-ABLIS≤0.1%.17例患者治疗满6个月时,均达CHR(100.0%);11例(64.7%)达CCyR;12例(70.6%)达BCR-ABLIS≤1%,其中4例(23.5%)达BCR-ABLIS≤0.1%.5例患者治疗满12个月,4例达CCyR;2例BCR-ABLIS≤1%,2例BCR-ABLIS≤0.1%,1例BCR-ABLIS>10%.血液学不良反应:3/4级白细胞减少、血小板减少和贫血发生率分别为20.9%、23.3%和16.3%.非血液学不良反应发生率分别为水肿76.7%,恶心呕吐51.2%,骨关节肌肉酸痛39.5%),皮疹20.9%,发热11.6%,腹泻11.6%,肝功能损害2.3%.无4/4级血液学与非血液学不良反应.结论 国产甲磺酸伊马替尼治疗初诊CML-CP患者的近期疗效肯定,不良反应可耐受,但仍需长期观察研究.     

Pharmacologic characterization of fluzoparib,a novel poly(ADP‐ribose) polymerase inhibitor undergoing clinical trials

Poly(ADP‐ribose) polymerase (PARP) enzymes play an important role in repairing DNA damage and maintaining genomic stability. Olaparib, the first‐in‐class PARP inhibitor, has shown remarkable clinical benefits in the treatment of BRCA‐mutated ovarian or breast cancer. However, the undesirable hematological toxicity and pharmacokinetic properties of olaparib limit its clinical application. Here, we report the first preclinical characterization of fluzoparib (code name: SHR‐3162), a novel, potent, and orally available inhibitor of PARP. Fluzoparib potently inhibited PARP1 enzyme activity and induced DNA double‐strand breaks, G₂/M arrest, and apoptosis in homologous recombination repair (HR)‐deficient cells. Fluzoparib preferentially inhibited the proliferation of HR‐deficient cells and sensitized both HR‐deficient and HR‐proficient cells to cytotoxic drugs. Notably, fluzoparib showed good pharmacokinetic properties, favorable toxicity profile, and superior antitumor activity in HR‐deficient xenografts models. Furthermore, fluzoparib in combination with apatinib or with apatinib plus paclitaxel elicited significantly improved antitumor responses without extra toxicity. Based on these findings, studies to evaluate the efficacy and safety of fluzoparib (phase II) and those two combinations (phase I) have been initiated. Taken together, our results implicate fluzoparib as a novel attractive PARP inhibitor.     

FOLFIRI方案治疗常规化疗失败晚期大肠癌的疗效分析

目的：探讨FOLFIRI方案治疗常规化疗失败晚期大肠癌患者的临床疗效和不良反应。方法：常规化疗失败的晚期大肠癌患者25例,开普拓（Irinotecan,CPT-11）180mg／m^2,静脉滴注,d1;FA200mg／m^2,静脉滴注,d1-2;5-FU400mg／m^2静脉推注,然后5-FU 600mg／m^2持续静脉滴注22h,d1-2,每2周重复,2次为1个周期,共行1—6个周期,中位周期1．5个。结果：25例患者,PR9例,SD10例,PD6例,总缓解率36．0％,中位缓解时间3．0—13．5个月。主要不良反应为迟发性腹泻和中性粒细胞减少,Ⅲ-Ⅳ度发生率分别为25．6％（11／43）和41．9％（18／43）。结论：FOLFIRI方案是治疗常规化疗失败晚期大肠癌的有效化疗方案,缓解率较高,迟发性腹泻和中性粒细胞减少为其主要不良反应。